Bicyclic [3.3.0]-Octahydrocyclopenta[c]pyrrolo Antagonists of Retinol Binding Protein 4: Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt Disease

  • J Med Chem. 2015 Aug 13;58(15):5863-88. doi: 10.1021/acs.jmedchem.5b00423.
Christopher L Cioffi ,  Boglarka Racz  1 ,  Emily E Freeman ,  Michael P Conlon ,  Ping Chen ,  Douglas G Stafford ,  Daniel M C Schwarz ,  Lei Zhu ,  Douglas B Kitchen ,  Keith D Barnes ,  Nicoleta Dobri  1 ,  Enrique Michelotti  2 ,  Charles L Cywin  3 ,  William H Martin  4 ,  Paul G Pearson  5 ,  Graham Johnson  5 ,  Konstantin Petrukhin  1
Affiliations
  • 1. §Department of Ophthalmology, Columbia University Medical Center, New York, New York 10032, United States.
  • 2. #National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, United States.
  • 3. ○National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, United States.
  • 4. ⊥WHM Consulting LLC, 111 Sterling City Road, Lyme, Connecticut 06371, United States.
  • 5. ∥iCuraVision LLC, 31194 La Baya Drive, Suite 101, Westlake Village, California 91362, United States.
PMID: 26181715 DOI: 10.1021/acs.jmedchem.5b00423
Abstract

Antagonists of retinol-binding protein 4 (RBP4) impede ocular uptake of serum all-trans retinol (1) and have been shown to reduce cytotoxic bisretinoid formation in the retinal pigment epithelium (RPE), which is associated with the pathogenesis of both dry age-related macular degeneration (AMD) and Stargardt disease. Thus, these agents show promise as a potential pharmacotherapy by which to stem further neurodegeneration and concomitant vision loss associated with geographic atrophy of the macula. We previously disclosed the discovery of a novel series of nonretinoid RBP4 antagonists, represented by bicyclic [3.3.0]-octahydrocyclopenta[c]pyrrolo analogue 4. We describe herein the utilization of a pyrimidine-4-carboxylic acid fragment as a suitable isostere for the anthranilic acid appendage of 4, which led to the discovery of standout antagonist 33. Analogue 33 possesses exquisite in vitro RBP4 binding affinity and favorable drug-like characteristics and was found to reduce circulating plasma RBP4 levels in vivo in a robust manner (>90%).

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